Humanized model of kidney and liver disorders

A method for assessing the in vivo therapeutic efficacy of an agent for use in a treatment of a complement-related nephropathy, the method comprising:

• (a) administering the agent to a mouse whose genome comprises a replacement at an endogenous mouse C3 locus to form a modified C3 gene,
• wherein the replacement is (i) a replacement of a mouse gene sequence comprising exon 1 through exon 41 of the mouse C3 gene with a nucleic acid sequence comprising exon 1 through exon 41 of the human C3 ene, or (ii) a replacement of a mouse gene sequence comprising exon 2 through exon 41 of the mouse C3 gene with a nucleic acid sequence comprising exon 2 through exon 41 of the human C3 gene,
• wherein expression of the modified C3 gene is under control of mouse regulatory elements at the endogenous mouse C3 locus, wherein the mouse spontaneously exhibits one or more symptoms of the complement-related nephropathy;
• and
• (b) measuring the one or more symptoms of the complement-related nephropathy in the mouse, and categorizing the agent as a therapeutic agent for treating the complement-related nephropathy when the agent inhibits the one or more symptoms of the nephropathy compared to control mice who have not been administered the agent,
• wherein the one or more symptoms of the nephropathy are selected from the group consisting of
• (i) one or more of glomerulonephritis, basophilic tubules, sclerotic glomeruli, dilated tubules with protein casts, mesangial matrix expansion, glomerular hypertrophy, mononuclear interstitial inflammation,
• (ii) C3 protein deposition in the kidney,
• (iii) deposition of C5b-9 membrane attack complexes in the kidney,
• (iv) one or more of elevated blood urea nitrogen (BUN), serum lipase, serum cystatin C, or serum non-high density lipoproteins, and
• (v) increased urinary albumin or C5a.